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Oncolytic Viruses in Gastric Cancer Treatment

Oncolytic virus therapy (OVT) has recently been the focus of extensive oncology research and shown success in preclinical and clinical testing as a novel cancer treatment modality with high safety profiles and low off-target toxicities. OVT is also called oncolytic virotherapy, viral therapy, and virotherapy whose antitumor action is based on the destructive nature of viruses to kill tumor cells in cancer patients. Therefore, the ultimate aim of OVT is to design a virus which can effectively replicate within the host, specifically target and lyse tumor cells and induce robust, long-lasting tumor-specific immunity.

Gastric Cancer

Gastric cancer (GC), also called stomach cancer, is the second leading cause of death from cancer worldwide. This deadly disease is characterized by a growth of cancerous cells within the lining of the stomach, but shows heterogeneity with epidemiologic and histopathologic differences across countries. GC is difficult to diagnose because most people typically don’t show symptoms in the earlier stages, resulting in late diagnosis, suboptimal therapies and poor survival rate.

Gastric cancer. Fig.1 Gastric cancer.

Oncolytic Viruses in GC

There are a number of viruses that can be used to play oncolytic functions in GC therapy, mainly including adenovirus (Ad), vaccinia virus (VACV or VV), herpes simplex virus (HSV). They present either naturally tumor-selective or can be modified to specifically target and eliminate tumor cells. During oncolytic virotherapy, specificity is imperative in order to reduce the side effects.

Overview of oncolytic viral therapy. Fig.2 Overview of oncolytic viral therapy. (Howells, 2017)

Final viral construct or viral-based strain Vector modifications Details
AdCEAp/Rep CEA promoter (conditionally replicating) Cytotoxicity against CEA-producing cells was dose-dependent and different from CEA-negative cells
AdE2F-p16 p16-expression cassette was inserted upstream of the E2F promoter, Data were normalized with those of CMV promoter Tumor-inhibition rate in xenografts was 59%
Ad5/35 Fiber shaft and knob from Ad35 into Ad5, E1B deleted SG235-TRAIL More efficient cell entry
Ad-hTERT-E1A-apoptin Ad under hTERT promoter with E1A and apoptin Ad-hTERT-E1A-apoptin resulted in complete response to treatment
Telomelysin OBP301 hTERT promoter, Deleted 55 kDa-encoding E1B region OBP-301 induced cell-cycle mobilization from G0–G1 to S/G2/M phases and subsequent cell death in quiescent CD133+ cancer stem-like cells by mobilizing cell-cycle-related proteins
E1B55KD (Addl1520)
Endostatin
Ad-Endo
Deleted 55 kDa-encoding E1B region, Expressing endostatin Selective replication and expression of endostatin in gastric cancer cells achieved synergistic effect

Table.1 Oncolytic adenovirus trials for gastric cancer.

Final viral construct or viral-based strain Vector modifications Details
Vaccinia GLV1 h153 Expressing Ruc-GFP fusion protein
Encoding rTFR, hNIS
Encoding thymidine kinase and hemagglutinin
Tumor regression over a 4-week period, with one animal with total regression

Table.2 Oncolytic VACV trials for gastric cancer.

Final viral construct or viral-based strain Vector modifications Details
HSV1 G207
NV1020
G207: deletion of both copies of γ1 34.5 genes and inactivation of ICP6 gene
NV1020: deletion of one copy of γ1 34.5 and intact ICP6 gene
In vitro studies were similar, with NV1020 having better results at lower viral concentrations
HSV1 NV1066 Early gene copies of ICP0 and ICP4 and the γ1 34.5 gene Exposure to NAC promoted killing
HSV (T-TSP1) Expressing TSP1 Arming the virus attenuated its replication in some cell lines, but cytotoxicity was not affected
Enhanced inhibition of angiogenesis was observed

Table.3 Oncolytic HSV trials for gastric cancer.

Oncolytic Viruses Modification

The specificity of OVs often determines the success of therapy. There are various ways have been developed to improve the specificity of OVs, such as tumor-specific promoters (TSPs) for conditionally replicating, insertion and deletion of specific genes to improve recognition efficacy. Taking advantage of pathways that are upregulated in tumor cells and not healthy cells, we can engineer a virus that relies on such a pathway for successful infection thereby rendering the virus incapable of infecting healthy tissue.

OVs are being developed to address various malignancies (such as GC) with improved specificity and efficacy in cancer therapeutics.

Reference

  1. Howells, A.; et al. Oncolytic viruses-interaction of virus and Tumor Cells in the Battle to eliminate Cancer. Frontiers in oncology. 2017, 7: 195.

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